Head and Neck Pathol DOI 10.1007/s12105-012-0395-y

CASE REPORT

Oral Alveolar Soft Part Sarcoma in Childhood and Adolescence: Report of Two Cases and Review of Literature

Prokopios P. Argyris • Robyn C. Reed • J. Carlos Manivel • Dolores Lopez-Terrada • Jared Jakacky • Zuzan Cayci • Konstantinos I. Tosios • Stefan E. Pambuccian • Lester D. R. Thompson • Ioannis G. Koutlas

Received: 21 May 2012 / Accepted: 22 August 2012 Ó Springer Science+Business Media, LLC 2012

Abstract Alveolar soft part sarcoma (ASPS) constitutes a 13 year-old boys, along with a focused review of the lit- rare soft tissue malignant neoplasm comprising less than erature on intraoral ASPS in pediatric patients. 1 % of all soft tissue sarcomas. ASPS demonstrates a strong predilection for adolescents and young adults, with a Keywords Alveolar soft sarcoma Á Children Á female predominance reported. The head and neck region Oral cavity Á Tongue Á Pathology Á Immunohistochemistry Á is the most commonly affected region in pediatric patients Molecular Á ASPSCR1/TFE3 fusion Á Management with the tongue and orbit affected most commonly. Herein we present the clinical, radiographic, histopathologic, immunohistochemical and molecular features of two Introduction examples of ASPS affecting the oral cavity of 4 and Alveolar soft part sarcoma (ASPS) constitutes a rare malignant soft tissue neoplasm comprising 0.5–0.9 % of all P. P. Argyris Á K. I. Tosios soft tissue sarcomas [1]. Christopherson et al. [2] were first Department of Oral Pathology and Medicine, School of Dentistry, National and Kapodistrian to coin the term and although ASPS may occur at any age, University of Athens, Athens, Greece it demonstrates a strong predilection for adolescents and young adults [3] between 15 and 35 years of age [1]. ASPS & P. P. Argyris Á I. G. Koutlas ( ) arising in infants and children younger than 15 years is Division of Oral and Maxillofacial Pathology, School of Dentistry, University of Minnesota, considered rare [1, 4]. Although most ASPS occur in the 515 Delaware Street SE 16-206B, Minneapolis, MN, USA extremities, tumors occurring in childhood and infancy e-mail: [email protected] have a predilection for the head and neck region, especially the orbit and tongue [1, 5–8]. R. C. Reed Á J. C. Manivel Á S. E. Pambuccian Department of Laboratory Medicine and Pathology, University Herein we present the clinical, radiographic, histopath- of Minnesota Medical Center, University of Minnesota, ologic, immunohistochemical and molecular features of Minneapolis, MN, USA ASPS occurring in the tongue of a 4 year old boy and the buccal mucosa of a 13 year old boy, along with a literature D. Lopez-Terrada Á J. Jakacky Molecular Oncology Laboratory, Department of Pathology, review with emphasis on pediatric intraoral ASPS cases. Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA Materials and Methods Z. Cayci Department of Diagnostic Radiology, University of Minnesota Medical Center, University of Minnesota, Minneapolis, MN, Immunohistochemical evaluation was performed using anti- USA bodies against pan cytokeratin (Dako; monoclonal; AE1/ AE3), desmin (Ventana; monoclonal; DE-R-11 and/or Dako, L. D. R. Thompson Department of Pathology, Woodland Hills Medical Center, D33), S100 protein (Ventana; polyclonal), HMB45 (Dako, Woodland Hills, CA, USA monoclonal, HMB-45), Melan-A (Dako, monoclonal, A103), 123 Head and Neck Pathol neuron specific enolase (NSE) (Ventana; BBS/NC/V1-H14), The lesion was discovered serendipitously by the child’s synaptophysin (Ventana, polyclonal), chromogranin parents. The patient’s medical history was unremarkable. (Ventana, monoclonal, LK2H10), CD68 (Ventana; KP1), Clinical examination revealed a firm, raised, well circum- MYOD1 (Dako; monoclonal, DAS), vimentin (Ventana, scribed, nontender, bluish mass located in the left dorsal monoclonal, V9), smooth muscle actin (Leica, monoclonal, side of the tongue, at the junction of the anterior two thirds asm-1), smooth muscle myosin heavy chain (Dako, mono- and posterior third. The tumor measured approximately clonal, SMMS-1), TFE3 transcription factor (Cell Marque; 2 cm in greatest dimension. No lingual motor disturbances monoclonal; MRQ-37). All immunohistochemical stains were present. There were no enlarged lymph nodes in the were performed on a Ventana NexES automated immuno- neck, supraclavicular or axillary areas. histochemistry system (Ventana Medical Systems, Tucson, With a clinical differential diagnosis of a benign mesen- AZ) according to the manufacturers’ instructions. chymal neoplasm, such as hemangioma, lymphangioma and To detect a ASPSCR1/TFE3 fusion, reverse-transcrip- rhabdomyoma, the patient underwent computed tomography tion polymerase chain reaction (RT-PCR) was performed which disclosed a 1.6 cm 9 1.4 cm 9 1.2 cm well-defined on total RNA extracted from paraffin-embedded tumor hyperdense lesion in the left superior aspect of the oral ton- tissue (RecoverAllTM Total Nucleic Acid Isolation Kit; gue, elevating the superior lingual edge (Fig. 1a, b). An Ambion Diagnostics). The SuperScript III First-Strand excisional biopsy was performed under general anesthesia. Synthesis System by Invitrogen was utilized followed by Histopathologic examination at low magnification end point PCR amplification, using previously reported revealed an infiltrating lesion with solid nodular growth pat- primers [9] and appropriate controls. The thermocycling tern extending and partially infiltrating the subjacent skeletal amplification conditions consisted of 1 cycle at 95 °C for muscle (Fig. 2, left). At medium magnification, the neoplastic 10 min, 54 °C for 1 min, 72 °C for 1 min, 15 cycles at cells were arranged in uniform sheets separated by thin septa 95 °C for 30 s, 54 °C for 1 min, 72 °C for 1 min, 21 cycles of vascularized fibrous connective tissue, with focal organoid at 95 °C for 30 s, 54 °C for 1 min, 72 °C for 2 min and nested architecture, but no alveolar pattern. The tumor cells finally 1 cycle at 95 °C for 30 s, 54 °C for 1 min and 72 °C were round or polygonal and were characterized by one or two for 7 min. PCR products were run on a 2 % agarose gel to ovoid vesicular nuclei with numerous prominent nucleoli and visualize the presence of a fusion product using ethidium low mitotic rate (4 per 10 HPFs). The cytoplasm varied from bromide staining. Five millilitre of the final amplification intensely eosinophilic to finely granular (Fig. 3b) or clear product was sequenced with the corresponding primers in (Fig. 3c). Crystalloid PAS-positive, diastase resistant cyto- the forward and reverse directions, using the ABI PRISM plasmic inclusions were present focally. Dye Terminator Cycle Sequencing Analyzer. The electro- The neoplastic cells demonstrated diffuse intense pherograms were edited and analyzed by utilizing the nuclear positivity for TFE3 and diffuse moderate to intense Chromos software. DNA sequence breakpoint analysis was cytoplasmic positivity for NSE. Focal CD68 cytoplasmic performed using BLAST sequence similarity searches staining was also observed (Fig. 4d). There was no staining (National Center for Biotechnology Information database). for cytokeratin AE1/AE3, desmin, or S-100 protein. A review of the English literature based on a MEDLINE The TFE3 nuclear staining suggested translocation search from 1966 to 2012 was performed and all cases of involving the TFE3 gene. RT-PCR demonstrated the ASPS involving the oral cavity specifically were included presence of an ASPSCR1/TFE3 fusion transcript, that in the review (Table 1). However, cases were excluded if commonly results from the t(X;17) translocation, and is the lesion arose primarily in the soft tissues of the upper characteristic of alveolar soft part sarcoma (Fig. 5). neck, or involved the sinonasal tract at the time of pre- The initial biopsy material featured involvement of the sentation. Clinical series were selected if critical informa- superior, medial and lateral margins by neoplastic nests thus tion about oral cavity tumors was included, but excluded if necessitating re-excision. No residual neoplasm was identi- the information was too generalized. Duplicate reports fied in the subsequent wider local excision and the patient’s were excluded from further evaluation. No foreign lan- postoperative course was uneventful. Postoperative imaging guage articles were included. studies, including computed tomography of the thorax, abdomen, and pelvis, and MRI of the brain, showed no metastatic lesions. The patient has remained in good health Case Reports and is disease-free 7 months after the initial diagnosis.

Case 1 Case 2

A previously healthy 4 year-old boy was referred for A 13 year-old boy noted a rapidly enlarging mass of the evaluation of an asymptomatic mass of the dorsal tongue. left posterior buccal mucosa, at the occlusal line, about 123 Head and Neck Pathol

Table 1 Reported pediatric cases of oral cavity ASPS No Author Years Age (years) Sex Location Tumor size (cm) Follow-up (years) Clinical course

1 Christopherson [2] 1952 12 F Base of tongue 5 8 NED 2 Caldwell [16] 1956 4 F Base of tongue 4 1 DOD/M 3 Vakil [17] 1963 10 F Posterior tongue N/R 0.5 DOD/R 4 Buchanan [18] 1975 17 F Infratemporal fossa 6 4 DOD/M 5 Olson [19] 1976 5 F Tongue, NOS 3 15 NED 6 Ramanjaneyulu [20] 1977 12 F Base of tongue 4 3 NED 7 Spector [21] 1979 17 F Base of tongue 4.8 3 DOD/M 8 Master [22] 1979 4 F Tongue, NOS N/R 15 DOD/M 9 King [23] 1983 5 F Tongue, NOS N/R 7 NED 10 Chaudhry [24] 1984 3.3 F Dorsal tongue 2 N/R NP 11 Komori [25] 1984 11 F Base of tongue 2.5 5 NED 12 Sawyer [26] 1985 16 F Tongue, NOS N/R 0.6 NED 13 Simmons [5] 1989 1.6 F Dorsal tongue 1.5 2.8 NED 14 Cetik [27] 1989 13 F Tongue, NOS 1.5 1.5 NED 15 Matsuno [28] 1990 6 M Tongue, NOS 3 2.3 AWD/M 16 Marker [29] 1995 17 F Mandibular angle 4.5 19 NED 17 Hunter [7] 1998 3 F Tongue, NOS N/R 4 N/R 18 Bentley [30] 1999 5 F Base of tongue 2.2 2 NED 19 Castle [31] 1999 3 M Tongue, NOS 0.8 4 NED 20 Yoshida [32] 2000 2 F Dorsal tongue 2 7.2 NED 21 Noussios [33] 2002 3 M Tongue, NOS 3.3 3.5 NED 22 Richards [34] 2003 16 M Mandibular angle N/R 1.3 NED 23 Inci [35] 2004 17 NP Tongue, NOS N/R 3 NED 24 Fanburg-Smith [8] 2004 3 F Dorsal tongue 2.5 11 NED 25 Fanburg-Smith [8] 2004 3 F Lateral border of tongue N/R 10 NED 26 Fanburg-Smith [8] 2004 5 M Base of tongue N/R 11 NED 27 Fanburg-Smith [8] 2004 5 F Midportion of tongue 1 22 NED 28 Fanburg-Smith [8] 2004 5 F Dorsal tongue N/R N/R N/R 29 Fanburg-Smith [8] 2004 6 M Tongue, NOS N/R N/R N/R 30 Fanburg-Smith [8] 2004 6 M Dorsal tongue 2.5 28 NED 31 Fanburg-Smith [8] 2004 7 M Ventral tongue 1.3 27 NED 32 Fanburg-Smith [8] 2004 7 M Dorsal tongue 2.5 16 NED 33 Fanburg-Smith [8] 2004 17 M Posterior tongue 2.5 25 NED 34 do Nascimento [6] 2005 13 F Tongue, NOS 3 5 NED 35 Kim [36] 2005 16 M Tongue, NOS N/R 0.5 NED 36 Kim [36] 2005 4 F Tongue, NOS N/R 0.7 NED 37 Correia-Silva [37] 2006 17 F Tongue, NOS 2 1 NED 38 Rodriguez-Velasco [4] 2008 2 F Tongue, NOS 1.5 2.8 NED 39 Kumar [38] 2010 7 M Tongue, NOS 2.5 0.9 NED 40 Present case #1 2012 4 M Dorsal tongue 2 0.6 NED 41 Present case #2 2012 13 M Buccal mucosa 3.2 1.0 NED N/R not reported, NED no evidence of disease, DOD dead of disease, R recurrent, M metastatic, AWD alive with disease

2 months after a well-child examination. The patient stated pelvis. A 1.5-cm level IIA lymph node was palpable on that the lesion ‘‘popped’’ and bled. Computed tomography physical examination. A biopsy was performed. (CT) scans showed a mass medial to the angle of the left Microscopic examination revealed a lobulated soft tis- mandible measuring 3.2 cm in great dimension. No sue tumor below an intact oral squamous mucosa (Fig. 2, abnormalities were found on CT of the abdomen and right) composed of large, round to polygonal cells with

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Fig. 1 Computed tomography findings. a Coronal view depicted well delineated hyperdense nodular mass (arrow) on the left aspect of the tongue dorsum. b Axial view of the mass (arrow)

Fig. 2 Low power appearance of the tumor. Left note the lobular architecture of the proliferation of neoplastic cells. The tumor cell sheets are separated by thick fibrous septae. Right note lobules of proliferating neoplastic cells infiltrating the skeletal muscle supporting the buccal mucosa and separated by delicate fibrous septae

eosinophilic to clear cytoplasm, mild nuclear pleomor- positivity (Fig. 4c), focal weak or patchy desmin positivity, phism, prominent nucleoli and 5 mitoses per 20 HPFs. The selective cytoplasmic staining of various intensity with tumor cells were arranged in nests, sheets and rare acinar- CD68 and no staining for cytokeratin AE1/AE3, vimentin, like structures (Fig. 3a), separated by a delicate meshwork smooth muscle actin, smooth muscle myosin heavy chain, of capillaries. There was no necrosis. Eosinophilic granular melanocytic markers S-100, HMB45, Melan-A, and neuro- material was present in the cytoplasm of some of the tumor endocrine markers synaptophysin and chromogranin. cells and crystals were highlighted with PAS, with RT-PCR demonstrated the presence of an ASPSCR1/ (Fig. 3d) and without diastase, and phosphotungstic acid TFE3 fusion transcript, quite characteristic of ASPS. hematoxylin (PTAH). The tumor involved minor salivary Based on the initial biopsy showing positive margins, a glands and infiltrated skeletal muscle but was not con- wide local re-excision accompanied by an ipsilateral nected to the surface epithelium. There was also perineural modified radical neck dissection was performed, with and angiolymphatic invasion. The bone was not involved, residual tumor present, but negative lymph nodes. The but the initial biopsy had positive margins. patient received adjuvant chemotherapy consisting of Immunohistochemical stains revealed strong diffuse ifosfamide and doxorubicin hydrochloride (COG ARST nuclear staining for TFE3 transcription factor (Fig. 4a), 0332 trial). The patient has remained in good health and is diffuse cytoplasmic NSE (Fig. 4b) and MYOD1 cytoplasmic disease-free 12 months after the initial diagnosis.

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Fig. 3 Histologic features of the tumor. a Low power appearance open chromatin and prominent nucleoli, ample clear to faintly showing, in this portion of the tumor, thick fibrous septae separating eosinophilic cytoplasm, and intracytoplasmic granular eosinophilic sheets of neoplastic cells with no appreciable ‘‘alveolar’’ pattern. material. d PAS stain after diastase digestion showing positivity of the b Tumor cells with small, ovoid nuclei and granular cytoplasm, cytoplasmic granules simulating granular cell tumor. c Tumor cells with large nuclei with

Fig. 4 Immunohistochemical findings. a TFE-3 showing nuclear staining. b Diffuse cytoplasmic staining with NSE. c Cytoplasmic staining with MYOD1. d Focal cytoplasmic staining with CD68

Discussion Lieberman et al. [10] reviewed the clinical and histopath- ologic features of 102 cases of ASPS. In their study the ASPS is an uncommon malignant soft tissue neoplasm, median age at diagnosis was 22 years (range 2–71 years) most commonly involving the lower extremities [1]. and the female to male ratio 1.5:1, with a higher F:M ratio

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Fig. 5 RT-PCR findings: identification of the ASPSCR1(ASPL)/TFE3 fusion transcript product in the tumor tissue

in childhood and adolescence. ASPS arises in association significant prognostic factors, with primary tumors mea- with skeletal muscle or musculofascial planes, a fact that suring less than 5 cm and those occurring in patients in the explains the strong predilection of this tumor for the thighs, first and second decades of life demonstrating a more buttocks and abdominal or chest walls [10]. The neoplasm favorable clinical course [10, 11]. is often indolent and may therefore be present for years ASPS arising in the oral cavity are exceedingly rare in before medical attention is sought [11]. Even then treat- the general population [8]. Data from the files of the Armed ment may be delayed as the highly vascularized mass of Forces Institute of Pathology (AFIP) between 1970 and ASPS is clinically misinterpreted as a benign or develop- 2003 showed that only 13 out of 266 cases of ASPS mental lesion such as a hemangioma, lymphangioma or (approximately 5 %) occurred in the tongue [4, 8]. How- arteriovenous malformation [4]. ever, in infants and children, 25 % of head and neck ASPS Despite being a slow-growing tumor with an asymp- involve the tongue [14], this frequency increasing to 70 % tomatic course, ASPS demonstrates a disproportionate when the orbits are excluded [15]. Table 1 summarizes all frequency of distant metastases even at the early stages of reported cases of intraoral ASPS in the pediatric population disease [12]. In fact, data reviewed by Enzinger and Weiss (0–18 years) [2, 4–8, 16–38], totaling forty-one cases, [13] revealed high metastatic potential of the tumor, with including the present series. There were 26 females and 14 13/36 patients (36 %) presenting early metastases before males affected, with a median age at diagnosis of 8.4 years, the detection of the primary. The frequency of metastasis at ranging from 1.6 to 17 years. In one case the gender of the presentation increases with the patient’s age at diagnosis patient was not provided [35]. The most common intraoral [10]. Metastases occur most commonly in the lungs, fol- location was the tongue accounting for 90.2 % (37/41) of lowed by bones and the brain [11, 13]. ASPS has the the cases, followed by the mandibular angle (4.8 %, 2/40), strongest predilection for brain metastasis of all sarcomas the buccal mucosa (2.4 %, 1/41) and infratemporal fossa [13]. (2.4 %, 1/40). Among the lingual cases of ASPS, the dorsal The 5-year-survival rate of ASPS in children, adoles- surface and the base of the tongue were affected in 21.6 % cents and adults younger than 25 years is reportedly 83 % (8/37) and 18.9 % (7/37) of the cases, respectively. In [11]. However, because of the propensity to late metastasis, 17/37 cases, the specific location of the tumor within the survival rates decline steadily. In the large series of adults tongue was not provided. The tumor size was reported in and children reported by Lieberman et al., [10] patients 28 cases and ranged from 0.8 to 6 cm (mean, 2.7 cm). The without metastases at presentation had survival rates of median period of follow-up after complete surgical treat- 77 % at 2 years, 60 % at 5 years, 38 % at 10 years and ment with or without supplementary chemotherapy and/or 15 % at 20 years. In that study, the local recurrence rate radiation therapy was 7.2 years (range 0.5–28 years). The after adequate excision of the primary tumor was 16.7 % majority of patients (31/41, 76 %) were alive with no [10]. Tumor size and age at diagnosis were identified as evidence of disease during the provided follow-up period.

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One patient was alive with metastases 2.3 years after the rod-like or rhomboid-shaped crystalline inclusions within initial diagnosis, and 5/41 (12.2 %) had died of dissemi- the cytoplasm of the tumor cells. These crystalline inclu- nated ASPS with distant pulmonary, cerebral or skeletal sions are found in 25–100 % of cases [8, 39], both in pri- metastases or from a recurrence of the primary tumor. In mary and metastatic ASPS. PAS positive diastase resistant 4/41 patients, information on the clinical course was granules may represent precursors to the rod shaped crys- unavailable. tals. The cell surface and cytoplasm in the region of these Compared to ASPS of the extremities, oral ASPS dem- crystals stains for MCT1 and CD147 [1, 14, 15]. MCT1, onstrates distinct clinicopathologic characteristics [4, 8]. the monocarboxylate transporter 1, is found predominantly First, the median age of patients with extremity ASPS is in cardiac and skeletal muscle, and catalyzes the rapid around 20 years, while oral ASPS affects a younger popu- transport of monocarboxylates from the rough endoplasmic lation, with a reported median age of 5 years [8]. Secondly, reticulum across plasma membranes. CD147 functions, in the reported cases of oral ASPS show a higher female pre- part, as its chaperone protein [1, 40]. dominance than ASPS of the extremities [4, 7, 8]. The size of The histogenesis of ASPS remains obscure [1, 5, 8]. the tumors affecting the tongue is smaller (median, 2.5 cm) Historic designations of this neoplasm as malignant gran- than that of ASPS involving other parts of the body [4]. The ular cell myoblastoma, malignant granular cell tumor and smaller size of the tumors and shorter interval to diagnosis malignant nonchromaffin paraganglioma [41] reflect some may account for the overall better prognosis of oral ASPS of the proposed histogenetic derivations from neural or occurring in children and adolescents [4, 8]. Schwann cell, paraganglia, and skeletal muscle [12]. In an Histologically, ASPS is characterized by aggregates of effort to demonstrate a myogenic derivation of ASPS, the large polygonal or round mesenchymal cells with abundant characteristic crystalloids encountered in ASPS have been eosinophilic, granular or clear cytoplasm [1–5, 7–9]. The interpreted as being composed of Z-band muscle sub- cells contain one or more vesicular nuclei with several stances [42]. prominent nucleoli, mild pleomorphism, relatively few Recently, based on the fact that ASPS show t(X;17) mitoses and rare atypical mitoses. The neoplastic popula- (p11;q25) involving the TFE3 gene, commercially avail- tion is characterized by multinodular growth and mainly able antibodies against the internal region of the TFE3 gene exhibits an organoid, nested architecture, with neoplastic have been used to confirm the diagnosis of ASPS [43]. The cells separated by multiple variably thick septae of vas- antibody against TFE3 shows variably strong nuclear cularized dense connective tissue. The loss of intercellular positivity in the majority of ASPS. However, TFE3 is not cohesion, with neoplastic cells adhering only to the fibro- specific for this tumor, as it may stain the nuclei of granular vascular septae, results in a ‘‘pseudo’’-alveolar pattern cell tumor [44], paraganglioma, translocation related renal [1–4, 6–8, 10, 12]. However, this alveolar architecture is cell carcinomas and adrenocortical carcinoma [45, 46]. If not encountered in all cases [7, 8, 23, 28, 31]. As in one of there is doubt about the diagnosis based on clinical and the case presented herein, a solid, ‘‘non-alveolar’’ pattern histological features, RT-PCR for the ASPSCR1/TFE3 was present, with the cells arranged in compact sheets and fusion transcript is a more specific method that can be cords without the characteristic dyshesion [8]. Based on the performed on frozen or paraffin-embedded tissue [44, 47]. observation that ASPS tumors in very young patients The der 17 t(X;17)(p11;q25)[48, 49] leads to rearrange- (B3 years old) exhibit a solid morphology while lesions in ment and fusion of ASPL and TFE3 genes. Two variants of older patients ([5 years old) acquire an organoid pattern, ASPSCR1/TFE3 gene fusion have been reported. Both Fanburg-Smith et al. [8] have suggested that the neo- encode a chimeric protein consisting of the ASPL N-terminal plasm’s architecture may be an age-related characteristic. region fused to TFE3 basic helix-loop-helix and leucine Specifically, they proposed that the ‘‘immature’’ neoplastic zipper DNA-binding domains. The expression of ASPSCR1/ cells form solid nests that become progressively dyshesive. TFE3 chimeric protein is considered to cause transcriptional A consistent finding in ASPS of the tongue is vascular deregulation and has been implicated as a possible tumori- invasion which has not been correlated with distant genic mechanism. Detection of t(X;17) or ASPL-TFE3 metastases or worse prognosis [8]. fusion transcripts are highly specific and sensitive markers ASPS are consistently negative for vimentin, cytokera- for rendering the diagnosis of ASPS [44, 50]. A study com- tins, and epithelial membrane antigen, neuroendocrine paring immunohistochemistry for TFE3 and CD147 to RT- markers (synaptophysin and chromogranin), and melano- PCR for ASPSCR1/TFE3 fusion transcript suggests that cytic markers. Desmin, S100 protein and NSE stains are identification of the ASPSCR1/TFE3 fusion transcript is the occasionally positive. There may be cytoplasmic but not most sensitive marker for diagnosing ASPS, surpassing the nuclear reaction with MYOD1. accuracy of immunohistochemical stain for TFE3 [44]. Of The pathognomonic histologic feature of ASPS, first crucial importance to this method is the extraction of ade- described by Masson [39], is the presence of granules and quate RNA from the paraffin embedded samples. If this is not 123 Head and Neck Pathol possible, fluorescence in situ hybridization (FISH) assay lipoblastoma or liposarcoma, but these are usually positive may be applied alternatively for the identification of TFE3 for S100 protein and show specific morphologic differences fusion gene [45, 51]. A similar but reciprocal t(X;17) such as lipoblasts, distinguishing them from ASPS [1]. Par- (p11;q25) translocation and ASPSCR1/TFE3 fusion tran- aganglioma shows a characteristic nested ‘‘zellballen’’ scripts have been identified in a variant of renal cell carci- architecture [47], and demonstrates positivity for neuroen- noma arising in pediatric and young adult patients [51, 52]. docrine markers, while S100 protein highlights the sup- Specifically, in our patients, imaging evaluation failed to porting sustentacular cells. identify any kidney lesions. Surgical excision of the tumor with negative margins is Depending on the predominant architectural pattern of considered the treatment of choice [5, 9, 18]. The benefit of the tumor (typical alveolar or solid, sheet-like), the dif- adjuvant therapy in ASPS is controversial but radiotherapy ferential diagnosis of ASPS encompasses a variety of and/or chemotherapy may be administered, and radiotherapy benign and malignant entities. Generally and traditionally, is particularly applied in cases of inadequate surgery [9]. the differential diagnosis includes rhabdomyoma, granular According to Lieberman et al., radio- and chemotherapy had cell tumor, PEComas, and, more remotely, clear cell sar- no statistically significant impact on the development of coma, renal cell carcinoma, extrarenal rhabdoid tumor, metastases [5]. ASPS prognosis is based mainly on clinical rhabdoid tumor of the kidney, hibernoma, other adipocytic features such as location of the primary lesion, size of the tumors, and paraganglioma [3, 5, 14, 41]. Adult rhabdo- tumor, and age of patient [1, 3, 5, 18]. ASPS can demonstrate myoma can be distinguished from ASPS by its large an early metastasizing potential, sometimes prior to detec- eosinophilic cells with small nuclei, the ‘‘spider-like’’ tion of the primary tumor, but can also metastasize decades appearance of the cytoplasm [1, 5, 40] and its characteristic after the initial diagnosis [1, 3–9, 15–20]. Hence, complete diffuse and strong cytoplasmic positivity for desmin and local excision, adjuvant therapy if clinically indicated, and nuclear positivity for MYOD1 and myf4. In contrast, ASPS long-term patient follow-up are advised for all cases of may exhibit variable cytoplasmic positivity for MYOD1 ASPS. Chemotherapeutic regimens used for the treatment of [53]. Both ASPS and granular cell tumor show granular other soft tissue sarcomas generally lack efficacy in ASPS. eosinophilic cytoplasm and round to polygonal cells. Treatments targeting the c-Met receptor (which is an However, while the nuclei of benign granular cell tumors ASPSCR1/TFE3 transcriptional target) with its downstream are uniform, without atypia or prominent nucleoli, ASPS effectors, AKT and ERK (which are activated in ASPS) shows nuclear atypia and prominent nucleoli. Granular cell with tyrosine kinase receptor inhibitors, novel c-Met tumors are intensely and diffusely positive with S100 inhibitors, and AKT inhibitors, as well as anti-angiogenic protein, while ASPS cells are usually S100 protein nega- drugs targeting the VEGF pathway have shown encour- tive. PEComas are rare neoplasms characterized by a aging preliminary results. proliferation of epithelioid or spindle cells with a perivas- cular distribution and dual myomelanocytic differentiation, Acknowledgments The authors are indebted to Mr. Jonathan resulting in positivity for both melanocytic markers such as Henriksen (University of Minnesota) for his superb assistance with the illustrations. HMB45, Melan-A and microphthalmia transcription factor, and muscle markers including SMA, muscle-specific actin and calponin [54]. ASPS are consistently negative for References melanocytic markers, which also helps their differentiation from clear cell sarcomas, which are positive for HMB45 as 1. Ordonez N, Ladanyi M. Alveolar soft part sarcoma. In: Fletcher well as S100 protein [55]. C, Unni K, Mertens F, editors. 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